The maintenance of fluid homeostasis is a critical parameter in establishing and maintaining normal physiology. Control of membrane water flux through membrane water pores (aquaporins; AQP) is essential for the ability of an organism to adapt to changing fluid environments. The function and regulation of individual AQP proteins is central to many physiological pathways including salivary secretion, urinary concentration, sweat production, and lung mechanics. Of specific interest to the study of lung mechanics is a member of this family, Aquaporin 5 (AQP5), and its functional role in mediating fluid regulatory mechanisms in the lung. Recent work has shown that AQP5 function is crucial in modulating bronchoconstrictive responses. Mice deficient in AQP5 are hyperresponsive to cholinergic-stimulated bronchoconstriction (narrowing of the airways), a clinical feature of asthma. Asthma is a common, complex genetic disease caused by a combination of inherited and environmental factors. Asthma affects nearly 15 million Americans, one third of them children. It is likely that not just one or a few, but rather several genes interact together, and with the environment, to elicit the hyperconstrictive airway response characteristic of clinical asthma. We do not currently understand how AQP5 functions normally in the lung, and why disruptions in this water channel results in an asthma-like pathophysiological state in mice. The proposed experiments use a combination of physiological, functional genomic and biochemical approaches to identify the pathways in which AQP5 is involved in maintaining proper lung fluid mechanics. Specifically, in vitro biochemical RNA processing assays will be used to determine the effects of AQP5 gene mutation on AQP5 gene expression. An AQP5-deficient mouse model of asthma will be used to identify the mechanistic genomic effects of AQP5 deficiency in the lung. This combinatorial approach will provide valuable information for the identification of new mechanistic pathways critical for the development of novel drug targets for the treatment of asthma.